Structural and functional consequences of c-N-Ras constitutively associated with intact mitochondria

• Published in: Biochimica et biophysica acta 2006-10, Vol.1763 (10), p.1108-1124
• Main Authors: Wolfman, Janice C., Planchon, Sarah M., Liao, Jinhui, Wolfman, Alan
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Mice; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitochondrial Membranes - metabolism; Mitochondrial stress; Morphology; Protein Isoforms; Ras; ras Proteins - chemistry; ras Proteins - genetics; ras Proteins - metabolism; ras Proteins - physiology; Retrograde signaling; Transcriptional activity
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2006.07.015

We demonstrate that both c-N-Ras and c-K(B)-Ras are constitutively associated with purified mitochondria. c-K(B)-Ras is associated with the mitochondrial outer membrane, and c-N-Ras is associated with both the outer membrane and inner mitochondrial compartments. The mitochondrial morphology is abnormal in both c-N-Ras negative and K-Ras negative cells. Normal mitochondrial morphology was restored by targeting N-Ras to both the inner and outer mitochondrial compartments, or by ectopically expressing c-K(B)-Ras. Impaired mitochondrial function can result in increased CHOP and NFκB activity, typical for a retrograde signaling response. Both are constitutively elevated in the N-Ras negative cells, but not in the K-Ras negative background, and are restored by c-N-Ras targeted exclusively to the inner mitochondrial compartment. Surprisingly, both targeting and the ability to functionally reduce retrograde transcriptional activity were found to be independent of c-N-Ras farnesylation. Overall, these data demonstrate for the first time a (1) farnesylation independent function for c-N-Ras and (2) that N-Ras within the inner mitochondrial compartment is an essential component of the retrograde signaling system between the mitochondria and nucleus.